EFFECT OF MULTIPLE DOSES OF KETOCONAZOLE ON CYTOCHROME P450 3A ACTIVITY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。细胞色素P450 (CYP) 3A酶是成人肝脏和小肠中最丰富的CYP酶。CYP3A酶参与了50%以上的代谢药物的生物转化。临床上观察到的许多药物-药物相互作用（DDI）是由这些酶的活性改变引起的。酮康唑是体内CYP3A活性的强抑制剂，可导致许多ddi，但目前尚不清楚这种作用是否在常用治疗剂量范围内是剂量依赖性的。临床试验的模拟表明，与每天400毫克一次，每天200毫克两次相比，患者可以从酮康唑中获得相同的治疗效果，并且药物相互作用更少，持续一周。然而，这些给药策略对酮康唑的DDI潜力尚未在人类中进行直接比较。我们计划以咪达唑仑为原型CYP3A底物，确定酮康唑400mg QD和200mg BID对肝脏和肠道CYP3A活性的影响。酮康唑是CYP3A4比CYP3A5更有效的抑制剂，后者具有多态性表达（33%的白种人和70%的非裔美国人）。因此，我们计划检查酮唑唑的抑制效力是否依赖于允许CYP3A5表达的基因型的存在。这将是24名健康志愿者的交叉研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cytochrome P450 (CYP) 3A enzymes are the most abundant CYP enzymes in adult human liver and small intestine. The CYP3A enzymes are involved in the biotransformation of more than 50% of all metabolized drugs. Many drug-drug interactions (DDI) observed clinically result from altering the activities of these enzymes. Ketoconazole is a strong inhibitor of CYP3A activity in vivo and results in many DDIs but it is unclear whether this effect is dose dependent within the range of doses commonly employed therapeutically. Simulations of clinical trials have suggested that patients may receive the same therapeutic benefit from ketoconazole and less drug interactions at 200 mg twice a day compared to 400 mg once a day for one week. However, the DDI potential of these dosing strategies for ketoconazole have not been directly compared in humans. We plan to determine the effect of ketoconazole 400 mg QD and 200 mg BID on hepatic and intestinal CYP3A activity using midazolam as a prototypical CYP3A substrate. Ketoconazole is a more potent inhibitor of CYP3A4 than CYP3A5 and the latter enzyme is polymorphically expressed (33% of Caucasians and 70% of African Americans). We therefore plan to examine whether the inhibitory potency of ketozonazole is dependent on the presence of genotypes that allow CYP3A5 expression. This will be a cross-over study in 24 healthy volunteers.